Management of Chronic Hepatitis B

1
Management of Chronic Hepatitis B C

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• ????? ?????
• ???? ???? - ????? ????
• ?????? ???????? ???????
• ???? 2008

2
Healthy Liver
3
Chronic Hepatitis B
4
Hepatitis B Virus
5
HBV Genome
4 Open Reading Frames - S S Pre S1 Pre
S2 - C C Pre C - P - X
6
Geographic Pattern of Hepatitis B Prevalence 1997
Source WHO, Geneva
7
Prevalence of HBV in Syria

• Intermediate HBV endemicity
• At least 4 of chronic infection
• Statistics of Blood Transfusion Centers
• Total Population of Syria 18 866 000 (2002)
• at least 750 000 Syrian with chronic HBV
  infection

8
Mode of Transmission of HBV in Syria

• Infected blood transfusion or blood products
• Needle stick injuries HCW - injection drug
  users
• Hemodialysis
• Sexual transmission heterosexual - homosexual
• Horizontal transmission childhood - family
  member
• Vertical Transmission (mother to newborn)
• Unsafe Procedures ear piercing-tattooing
  -barbering.

9
Natural History of Chronic Hepatitis B
10
Natural History of Chronic HBV Infection
CompensatedCirrhosis
Resolution
Stabilisation
Liver Cancer
AcuteInfection
ChronicHepatitis
Cirrhosis
Death
Chronic Carrier
Progression
DecompensatedCirrhosis (Death)
30 - 50 Years
Adapted from Feitelson, Lab Invest 1994
11
Chronic Hepatitis B

• 1. HBs Ag gt 6 months
• 2. Serum HBV DNA gt2.000 or 20.000 IU/mL
• 3. Persistent or intermittent elevation in
  ALT/AST
• 4. Liver biopsy showing chronic hepatitis
  necroinflammatory score ? 4

12
Types of Chronic HBV Infections

• Wild type HBe Ag chronic hepatitis
• Mutant type HBe Ag chronic hepatitis
• More prevalent in Syria
• Up to 70

13
HBe Ag HBe Ag Chronic Hepatitis

• HBe Ag HBe Ag
• HBs Ag
• HBe Ag
• Anti-HBe
• HBV DNA (IU/mL) gt 20. 000 gt 2.000
• (copie/mL) gt 100000
  gt10000
• ALT Elevated Elevated
• Necro-inflammation

14
Initial Evaluation of patients with chronic HBV

• 1. History physical examination
• 2. Laboratory tests for liver disease CBC
• Hepatic panel
• PT
• 3. Tests for HBV replication HBeAg /anti-HBe
  HBV DNA by PCR
• 4. R/O other causes of liver disease anti-HCV
• anti HDV

15
Indications of Liver Biopsy

• HBs Ag
• Chronic or intermittent elevations of ALT
• Candidate for treatment
• HBV DNA gt 2.000 or 20.000 IU/mL
• No contraindications for treatment

16
Results of Liver Biopsy

• Confirming diagnosis of chronic HB
• Grading severity of necroinflammation
• Staging the fibrosis
• Excluding other inter-current disease

17
Scoring Systems for Chronic Hepatitis
Maximum grade score Maximum stage score Comments
HAI (Knodell) 18 4 Original scoring system
Sheuer 4 4 1st to separate stage grade
METAVIR 4 4 Excellent
Modified HAI (Ishak) 18 6 Most widely used in USA UK
18
Increasing Severity of Inflammation (Grading)
Am J Surg Pathol 1995 19 1409 - 1417.
19
Progression of Fibrosis(Staging)
Am J Surg Pathol 1995 19 1409 - 1417.
20
Goal of Treatment of Chronic HBV

• HBe Ag
• Seroconversion of HBe Ag to anti-HBe
• HBe Ag
• HBV DNA lt 2.000 IU/mL
• Disappearance of HBs Ag is not the goal

21
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• ????????????(INF) ??? ????? 5 ????? ????/???
  10 ????? ???? 3 ????/?????
• ????? 6 ?????
  ????/?2 3 ????/?????
• ????? ??????????(PEG-INF) ??? ????? 180 ?????????
  ??? / ?????
• ???????????(LAM) ?? ???? ???? 100 ???/??? (????
  YMDD)
• ??????????(ADV) ?? ???? ???? 10 ???/??? (????
  ?????)
• ???????????(ENT) ?? ???? ???? 30
  ???/???
• ???????????(TDF) ?? ???? ???? 300
  ???/???

22
How when to assess the response to treatment?
23
Category of Response

• Biochemical (BR) Decrease in serum ALT to normal
  range
• Virological (VR) HBe Ag Loss of HBe Ag
• HBe Ag HBV DNA lt104 copies/ml
• Histological (HR) Decrease in HAI by at least 2
  points compared to pre-treatment liver biopsy
• Complete (CR) Biochemical virological response
• loss of HBs Ag

24
What are the predictive factors of response to
treatment?
25
Predictive Factors of Response to Therapy

• High level of ALT
• Low lever of HBV DNA
• Female patients
• Infection in adulthood
• Severe necro-inflammation activity in liver biopsy

26
Treatment of HBe Ag chronic hepatitis B

• IFN First choice
• ADF Contraindication to INF
• Intolerance to INF
• No response to INF
• ADF Lamivudine resistant mutants
• ENT
• TDF (First choice ESAL-2008)

27
???? ?????? ?????? ????? ?????? BHBeAg
HBeAg Positive
HBV DNA 20,000 IU/mL (105 copies/ml)
HBV DNA lt 20,000 IU/mL (105 copies/ml)
ALTelevated
ALT normal

• No treatment
• Monitor every 6-12 mos

• Monitor ALT every 3-12 mos (immune tolerant)
• Consider biopsy if age gt 35-40 yrs and treat if
  significant disease

• Treat
• Adefovir, entecavir, peginterferon, and Tenofovir
  are first-line options

Updated from Keeffe EB, et al. Clin Gastroenterol
Hepatol. 20064936-962.
28
Treatment of HBe Ag chronic hepatitis B

• IFN First choice
• ADF Contraindication to INF
• Intolerance to INF
• No response to INF
• ADF Lamivudine resistant mutants(YMDD)
• ENT
• TDF
• In view of the need for long term treatment, IFN
  or ADF, ENT, TDF is preferred

29
???? ?????? ?????? ????? ?????? BHBeAg-
HBeAg Negative
HBV DNA 2000 IU/mL (104copies/ml)
HBV DNA lt 2000 IU/mL (104copies/ml)
ALTnormal
ALTelevated

• No treatment
• Monitor every 6-12 mos

• Monitor ALT and HBV DNA or
• Consider biopsy since ALT often fluctuates and
  treat if significant disease

• Treat
• Adefovir, entecavir, peginterferon, and Tenofovir
  are first-line options
• Long-term treatment required (oral agents)

Updated from Keeffe EB, et al. Clin Gastroenterol
Hepatol. 20064936-962.
30
???? ????? ?????? ??????? ?????? ?? ?????? ????? B
HBV DNA (PCR)
HBV DNA 2000 IU/mL
HBV DNA lt 2000 IU/mL

• Treat with adefovir or entecavir
• May be a role for combination therapy
• Significant clinical consequences associated with
  lamivudine resistance in this population

• No treatment
• May choose to treat or observe
• If treat adefovir, entecavir, or combination
  treatment
• May be a role for combination therapy

Keeffe EB, et al. Clin Gastroenterol Hepatol.
20064936-962.
31
????? ??????

• 0

HBeAg
HBeAg-
?????? ????
?? ?????? ????
???? ?????? ??? 6-12 ?????
???? ?????
??????? ??????
Keeffe et al. Clin Gastroenterol Hepatol.
200427.
32
Side Effects of Interferon

• Influenza-like symptoms
• Alopecia
• Neutropenia thrombocytopenia
• Depression
• Induction of autoimmune disease (thyroid,.)
• Cardiac complication MI, AP
• Erythema at injection site
• Loss of libido
• Diabetes mellitus

33
Contraindications of Interferon

• Current psychosis or a history of psychosis
• Uncontrolled depressive illness
• Presence of active auto-immune disease
• Neutropenia or thrombocytopenia
• Decompensated cirrhosis
• Symptomatic heart disease
• Uncontrolled seizures

34
Follow-up of Patients on IFN Therapy

• CBC q 2 weeks to 8 weeks then q 8 weeks
• ½ dose WBC lt 1 500 / mm
• Neutrophils lt 750 / mm
• Platelets lt 50 000 / mm
• Stop WBC lt 1 000 / mm
• Neutrophils lt 500 / mm
• Platelets lt 25 000 / mm
• Thyroid tests q 3 - 4 months

35
Inactive HBs Ag Carrier State

• 1. HBs Ag gt 6 months
• 2. HBe Ag , anti-HBe
• 3. Serum HBV DNA lt 20.000 IU/mL
• 4. Persistently normal ALT/AST levels
• 5. Liver biopsy absence of significant hepatitis
• necroinflammatory score lt 4

Previously described as healthy carrier
state
36
Follow-up of Inactive HBs Ag Carrier State

• ALT q 6-12 months
• If ALT gt1-2 x ULN check serum HBV DNA level
• exclude other causes of liver disease
• Consider screening for HCC in relevant
  population
• ?FP US every 6 months

37
???? ?????? ????? ??????? ??????? ?????????
??????? ????? ????? ???? ?????
20 ??? HBeAg? ???? ?????? ???? ???? ?????
?????? ??? 6-12 ?????
????? ????? ???? ?????
??? ???? ?????? ???? ??? ???
????? ????? ???? ?????
Dienstag et al, N Engl J Med. 19993411256-1263.
Marcellin et al. N Engl J Med. 2003348808-816. C
hang et al. Hepatology. 200440(4 suppl)193A.
38
How to whom you give the vaccine of HBV?
39
Schedule of Vaccine
Standard 0, 1, 6 months
Rapid 0, 1, 2 months
Accelerated 0, 7, 21 days
Higher antibody levels after 3rd dose
Rapid protection 4th dose at 12 months for those
at intermediate risk
Rapid protection 4th dose at 12 months for those
at high-risk
40
Indications of HBV vaccine

• Universal All infants
• All children adolescents not vaccinated
• High risk group Health care workers
• Household contacts
• CRF hemodialysis patients
• Repeated blood transfusions
• Homosexuals
• Sexual partners of HBV carriers
• Illicit injection drug users

41
Adverse Events of Vaccine

• Minimal reactions
• Local pain only local pain more frequent in PCT
• Mild transient fever mostly lasting only 24 h
• Anaphylaxis
• Incidence 1 / 600 000 vaccine doses
• Epinephrine should always be available
• No severe or fatal anaphylactic reaction
  reported
• Demyelinating diseases
• Not support for causal relationship

42
Efficacy of HBV Vaccine Age

• Efficacy of the vaccine depends on age
• Newborns 100
• lt 20 years 95
• lt 40 years 90

43
Vertical Transmission

• Mother with HBsAg HBeAg
• 80 - 90 infected newborns
• 90 of infected infants become chronic
  carriers
• Mother with HBsAg HBeAg
• 15 infected newborns
• 90 of infected infants become chronic
  carriers

44
How to prevent the vertical transmission of HBV?
45
Active Passive Immunization

• Immediately after Delivery
• 1st dose Vaccine
• HBIG (200 IU)
• 1 month after delivery
• 2nd dose Vaccine
• 2 month after delivery
• 3rd dose Vaccine

in 2 different sites
46
Treatment of HBV Infection in Children

• Treated as adults with modification of doses
• IFN 6 MU / m2 3 times / week
• No more than 10 MU per dose
• LAM 3 mg / kg / day
• No more than 100 mg / day
• ADF Not yet approved for treatment in children

47
Treatment of HBV infection in CRF KT

• Data on all 4 agents are limited
• There are no guideline or consensus
• IFN CRF Indicated with surveillance
• KT Can lead to rejection
• LAM CRF Indicated with surveillance
• KT Indicated
• ADF Limited data with this drug
• TDF CRF Indicated with surveillance
• KT Indicated

48
HBs Ag Positive
ALT HBe Ag anti-HBe Diagnosis
Normal Immunotolerant phase
Very high Acute infection
High Chronic infection
High Chronic infection
Normal Inactive carrier state
49
Hepatology 2007 45 507 - 539.
50
Chronic Hepatitis C
51
HCV Genome
N Engl J Med, 2001 345 41 - 52
52
Natural History of HCV Infection
N Engl J Med, 2001 345 41 - 52
53
HCV Infection Worldwide Genotype Distribution
1a, 1b 2a, 2b, 2c, 3a
1a, 1b 2a, 2b, 3a
1b
2a
4
1b, 6
1b, 3a
4
3b
1a, 1b, 2b, 3a
1b, 3a
5a
Fang et al. Clin Liver Dis. 1997
54
Genotype Distribution
59
28
10
n 636
55
Utility of Diagnostic Tests in HCV
Assessing Predicting Length Response
Sustained Method Screen Confirmation of
Therapy to Therapy Response ALT/AST X Enzyme
Ximmunoassay (EIA) HCV RNA qualitative X Xassa
y HCV RNA quantitative X Xassay HCV
genotype X
CDC. MMWR. 1998.
56
Interpretation of Hepatitis C Testing

• Anti HCV HCV RNA Interpretation
• No infection
• HCV present
• Resolved infection
• Treated HCV
• lt detectable level
• AIDS
• Hemodialysis
• Early infection

Cleveland Clinic Journal of Medicine 2003 70
S7 - S13.
57
Algorithm for Laboratory Investigation of
Suspected HCV Infection
Cleveland Clinic Journal of Medicine 2003 70
S7 - S13.
58
Goals of Therapy in CHC

• No virus1
• Arrest progression(necrosis/fibrosis)
• No symptoms

Secondary objectivedelay/prevent
Primary objective cure

• Reduce progression of fibrosis1
• Reduce progression to cirrhosis2
• Prevent decompensation
• Prevent HCC2

1. Worman. Hepatitis C Sourcebook 2002 2.
Peters et al. Medscape HIV/AIDS eJournal.
20028(1).
59
Milestones in therapy of chronic hepatitis C
60
Available Drugs in CHC

• IFN 3 M units, 3 times weekly
• Peg-IFN
• - Peg-IFN ? 2a 180 ?gm weekly
• - Peg-IFN ? 2b 1.5 ?gm/kg weekly
• Ribavirin 800 - 1200 mg daily
• Combination therapy
• IFN or Peg-IFN with Ribavirin
• Monotherapy Special cases

61
Negative Predictive Factors of Response to
therapy in HCV

• Genotype 1
• High viral load
• Alcohol consumption1
• Older age at time of infection (gt40 years)1
• Male gender1
• Obesity
• Other co morbidities
• HIV/HCV coinfection2
• HBV/HCV coinfection3

1. Poynard et al. Lancet. 1997 2. Di Martino et
al. Hepatology. 2001 3. Lana et al. Med Clin
(Barc). 2001
62
Treatment of CHC Genotype 1/4

• Peg-IFN ? 2a 180 ?gm weekly or
• Peg-IFN ? 2b 1.5 ?gm/kg weekly
• Ribavirin 800 -1200 mg daily
• For 12 weeks EVR
• HCV-RNA
• PCR

63
Treatment of CHCSustained Virological Response
10
9
8
7
6
Log HCV RNA (IU/ml)
2-log decline
5
4
3
SVR
2
1
0
-6
0
6
12
18
24
30
36
42
48
54
60
66
72
78
Weeks
Detection limit (50 IU/ml)
64
Treatment of CHC Genotype 2/3

• Peg-IFN ? 2a 180 ?gm weekly or
• Peg-IFN ? 2b 1.5 ?gm/kg weekly
• Ribavirin 800 mg daily
• For 24 weeks - No need for EVR - SVR 80-82
• Or
• IFN 3 Million Unit 3 / week
• Ribavirin 1000 -1200 mg/d
• For 48 weeks if EVR achieved - SVR 79

65
Treatment of Acute Hepatitis C

• 20 recovery within 3 months
• Waiting 3 months before treatment
• IFN monotherapy for 6 months
• 5 M daily / 4 weeks followed by
• 5 M 3 Weekly / 20 weeks
• 98 of 44 patients had negative HCV-RNA by 24 w

Jaeckel et al. Treatment of acute hepatitis C
with interferon alpha-2b. N Engl J Med 2001 345
66
HCV Renal failure/dialysis

• High prevalence of HCV in dialysis units in Syria
• Anti-HCV may be negative
• Ribavirin is contra-indicated
• IFN monotherapy is the treatment
• Response to treatment is higher in CRF patients
  for the same genotype

67
HCV Renal failure/dialysis

• A tentative of viral eradication should be given
  before kidney transplantation
• If failed and if the liver functions are stable
  the liver biopsy doesnt show advanced liver
  disease, kidney transplantation is authorized

68
Treatment of Cirrhosis in CHC

• We treat if
• Bilirubine lt 1.5mg/dl
• Serum albumin gt 3.4 g/dl
• INR lt 1.5
• WBC gt 1500
• Platelets gt 75000
• No ascitis, no encephalopathy
• SVR 43

69
Treatment of CHCRelapse
10
9
8
7
6
Log HCV RNA (IU/ml)
2-log decline
5
Relapse
4
3
SVR
2
1
0
-6
0
6
12
18
24
30
36
42
48
54
60
66
72
78
Weeks
Detection limit (50 IU/ml)
70
Treatment of CHCNull Response
10
9
8
7
Null response
6
Log HCV RNA (IU/ml)
5
Relapse
4
3
SVR
2
1
0
-6
0
6
12
18
24
30
36
42
48
54
60
66
72
78
Weeks
Detection limit (50 IU/ml)
71
Treatment of CHCPartial Response
10
9
8
7
Null response
6
Log HCV RNA (IU/ml)
5
Relapse
4
Partial response
3
SVR
2
1
0
-6
0
6
12
18
24
30
36
42
48
54
60
66
72
78
Weeks
Detection limit (50 IU/ml)
72
Cirrhosis
73
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